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Joel Palefsky, M.D. Department of Medicine

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  • This diagram summarizes how VLP-based vaccines are made. The first step is to isolate the DNA of a naturally occurring HPV and then clone the gene or open reading frame (ORF) encoding the L1 capsid protein into a plasmid. The plasmid containing the L1 gene is then introduced into a eukaryotic cell, the L1 gene is transcribed into mRNA and the cell then translate the mRNA into L1 capsid proteins. These capsid proteins then combine together to form a viral like particle. Since no viral DNA (except for the L1 gene) has been introduced into the eukaryotic cell, there are no viral genomes available to incorporate with the viral like particles so there is no danger of producing infectious virions. The VLPs are then purified and used to elicit an immune response in the host.
  • Women enrolled in this Phase II study have continued to be followed. This graph presents the immunogenicity results for these women. The X-axis gives the time in months since enrollment and the Y-axis shows the geometric mean titers of neutralizing antibodies for HPV 16 identified in the serum of the women expressed in arbitrary units per ml of serum. The red line indicates the antibody titers among recipients of the HPV 16 L1 VLP vaccine and the blue line the titers in women who were found to be serologically positive at enrollment, but who were PCR negative for HPV 16 DNA at enrollment. After the first dose of vaccine given at enrollment the mean titers begin to increase and the continue to increase over the first six months. Note women received three dosages of vaccine. After the third dose of vaccine was administered vaccinated women had antibody levels almost two orders of magnitude greater than what occurs with naturally-occurring exposure. Over time there has been a minor reduction in mean antibody titers but even 42 months after the last dose of vaccine the titers in the vaccinated women appear to be approximately a log higher than is seen with naturally-occurring immune responses. This data is extremely encouraging since it suggests that the effects of the vaccine are likely to be highly durable. In a recent presentation to the ACIP this data was updated and effect now appears to be durable out to month 60 (5 years).
  • Transcript

    • 1. Joel Palefsky, M.D. Department of Medicine University of California, San Francisco May 7, 2007 Human Papillomavirus Vaccines and HPV-Associated Anogenital Disease in HIV-Seropositive Men and Women: A New Era?
    • 2. Outline  Summary of HPV-related neoplasia inSummary of HPV-related neoplasia in HIV-seropositive men and womenHIV-seropositive men and women  Impact of highly active antiretroviralImpact of highly active antiretroviral therapytherapy  Current screening guidelinesCurrent screening guidelines  Role of the HPV vaccineRole of the HPV vaccine
    • 3. Cervical Squamo-columnar Transformation Zone Active transformation zone External os Original squamo- columnar junction Active squamo- columnar junction Columnar epithelium Cervical cleft opening
    • 4. Percent with cervical HPV infection 0 10 20 30 40 50 60 70 80 CD4>500 500>CD4>200 CD4<200 p<0.001 HIV- HIV+ HIV+ HIV+
    • 5. Percent with abnormal cervical cytology 0 10 20 30 40 50 60 HIV- HIV+ HIV+ HIV+ CD4>500 500>CD4>200 CD4<200 p<0.001
    • 6. Anal and cervical cancer incidence  Cervical cancer prior to cervical cytologyCervical cancer prior to cervical cytology screening: 40-50/100,000screening: 40-50/100,000  Cervical cancer currently: 8/100,000Cervical cancer currently: 8/100,000  Anal cancer among HIV- MSM: 13-Anal cancer among HIV- MSM: 13- 35/100,00035/100,000  Anal cancer twice as high among HIV+Anal cancer twice as high among HIV+ MSM than HIV-MSMMSM than HIV-MSM
    • 7. 100 CD4>500 200-500 <200 HIV- HIV+ 80 60 40 20 Percent with anal HPV infection HIV+ HIV+
    • 8. 80 CD4>500 200-500 <200 HIV- HIV+ Percent with abnormal anal cytology 60 40 20 HIV+ HIV+
    • 9. Anal and cervical HPV infection in HIV-positive women 0 10 20 30 40 50 60 70 80 90 HIV- HIV+ CD4 >500 HIV+ CD4 200-500 HIV+ CD4 <200 Anal Cervical
    • 10. Immune suppression (adaptive and innate) Genetic changes HPV and HIV infection in the development of anogenital cancer HPV HPV HPV HIV Infection N Death LSIL HSIL Cancer Anogenital Disease
    • 11. HPV HPV HPV HIV Infection HAART LSIL HSIL LSIL N Anogenital Disease Decreased Incidence of Anogenital Cancer Increased Incidence of Anogenital Cancer Immune suppression Genetic changes HPV HPV HPV HIV Infection HAART HSIL LSIL N Anogenital Disease Effect of HAART on incidence of anal cancer
    • 12. Effect of highly active antiretroviral therapy on cervical and anal intraepithelial neoplasia CIN - 9 studiesCIN - 9 studies  4 positive, 4 negative, 1 mixed4 positive, 4 negative, 1 mixed AIN - 4 studiesAIN - 4 studies  3 negative, one positive3 negative, one positive
    • 13. Anal cancer since introduction of HAART  Chiao et al, JAIDS 2005 40:451-5Chiao et al, JAIDS 2005 40:451-5  Pre-HIV: 1973-1981 0.6/100,000Pre-HIV: 1973-1981 0.6/100,000  HIV: 1982-1995 0.8/100,000HIV: 1982-1995 0.8/100,000  HAART: 1996-2001 1.0/100,000HAART: 1996-2001 1.0/100,000  Female to male ratio 1.6:1 1.2:1Female to male ratio 1.6:1 1.2:1  Bowers et al, JAIDS 21:06:38 2004Bowers et al, JAIDS 21:06:38 2004  8640 HIV+ MSM in London8640 HIV+ MSM in London  Pre-HAART incidence- 35/100,000 patient-years (95% CI 15-72)Pre-HAART incidence- 35/100,000 patient-years (95% CI 15-72)  Post-HAART incidence-92/100,00 patient-years (95% CI 52-149)Post-HAART incidence-92/100,00 patient-years (95% CI 52-149)
    • 14. San Francisco AIDS Surveillance Registry- California Cancer Registry match  14,210 adults with AIDS diagnosed in 1990-200014,210 adults with AIDS diagnosed in 1990-2000  risk of anal cancer increased after 1995 (RH =risk of anal cancer increased after 1995 (RH = 2.9)2.9)  anal cancer survival slightly decreased (RH = 1.4)anal cancer survival slightly decreased (RH = 1.4)  Hessol NA et al.Hessol NA et al. Am J Epidemiol,Am J Epidemiol, 20072007
    • 15. Guidelines for assessment of CIN in HIV+ women  Pap smear at initial evaluationPap smear at initial evaluation  Repeat Pap smear 6 months laterRepeat Pap smear 6 months later  If both negative, can do annual PapIf both negative, can do annual Pap  Low threshold for colposcopy (ASCUSLow threshold for colposcopy (ASCUS and up)and up)
    • 16. U.S. anal screening guidelines “Although formal guidelines recommending anal Pap smear screening have not been adopted, certain specialists recommend anal cytologic screening for HIV-1-infected men and women. High-resolution anoscopy (HRA) should be considered if the anal Pap smear indicates ASCUS or ASC-H and should be performed if a person has LSIL or HSIL on anal Pap smear. Visible lesions should be biopsied to determine the level of histologic changes and to rule out invasive cancer.” Treating Opportunistic Infections among HIV- Infected Adults and Adolescents:Treating Opportunistic Infections among HIV- Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIVRecommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America, 2005Medicine Association/Infectious Diseases Society of America, 2005
    • 17. New York State Department of Public Health AIDS Institute Guidelines: Primary Care Approach ToGuidelines: Primary Care Approach To The HIV-Infected PatientThe HIV-Infected Patient “Like cervical cancer, invasive squamous cell cancers of the anal canal are associated with certain types of human papillomavirus (HPV) infection, most notably, HPV-16 and HPV-18. Although this is a new practice that may not be routinely available, screening for cellular dysplasia is prudent and recommended, particularly in persons at high risk for infection with papilloma viruses”
    • 18. New York State Department of Public Health AIDS Institute Genital and Rectal Examination Recommendations:  At baseline and as part of the annual physical examinationAt baseline and as part of the annual physical examination for all HIV-infected adults, regardless of age, cliniciansfor all HIV-infected adults, regardless of age, clinicians should:should: Inquire about rectal symptoms, such as itching,Inquire about rectal symptoms, such as itching, bleeding, diarrhea, or painbleeding, diarrhea, or pain  Perform a visual inspection of the anal regionPerform a visual inspection of the anal region  Perform a digital rectal examinationPerform a digital rectal examination
    • 19. New York State Department of Public Health AIDS Institute Anal cytology recommendations:  Clinicians should perform anal cytology at baseline and annually in the following populations:  Men who have sex with men  Any patient with a history of anogenital condylomas  Women with abnormal cervical/vulvar histology  Clinicians should refer patients with abnormal anal Pap test findings for high-resolution anoscopy and/or examination with biopsy
    • 20. Benefits of anal screening  Early in natural history- increased easeEarly in natural history- increased ease of treating small lesionsof treating small lesions  Mid-natural history- local vs. surgicalMid-natural history- local vs. surgical removalremoval  Infra-red coagulationInfra-red coagulation  65% free of disease after median of 413 days65% free of disease after median of 413 days  Late in natural history- monitoring toLate in natural history- monitoring to detect early development of cancerdetect early development of cancer
    • 21. Superficially invasive squamous cell carcinoma of the anus (SISCCA)  19 patients19 patients  No patients died of SCCANo patients died of SCCA  5 of 19 (26%) developed recurrent cancer5 of 19 (26%) developed recurrent cancer  3 were re-excised and remain cancer-free, 2 required RAC  No patients required a colostomyNo patients required a colostomy  17 of 19 (89%) developed recurrent HGD  Careful follow-up is essentialCareful follow-up is essential Berry, Jay and Palefsky, 2006
    • 22. Current unknowns  Will anal screening and treatment ofWill anal screening and treatment of AIN lower the incidence of anal cancer?AIN lower the incidence of anal cancer?  Is effective treatment of AIN possible?Is effective treatment of AIN possible?
    • 23. Future approaches to treatment  Therapeutic vaccines- not ready forTherapeutic vaccines- not ready for prime time, but with some futureprime time, but with some future potentialpotential  Preventive vaccines!Preventive vaccines!
    • 24. Bivalent VaccineBivalent Vaccine Quadrivalent VaccineQuadrivalent Vaccine ReferenceReference Harper DM et al., LancetHarper DM et al., Lancet 364:1757-1765, November 2004364:1757-1765, November 2004 Villa LL et al.,Villa LL et al., LancetLancet Oncology 2005;6:271-278.Oncology 2005;6:271-278. Vaccine TypeVaccine Type Bivalent HPV-16 and HPV-18Bivalent HPV-16 and HPV-18 VLP , L1 capsid componentVLP , L1 capsid component Quadrivalent HPV-6/11/16/Quadrivalent HPV-6/11/16/ 18 VLP, L1 capsid component18 VLP, L1 capsid component ManufacturingManufacturing Insect Cells (Baculovirus)Insect Cells (Baculovirus) YeastYeast ConcentrationConcentration 20 µg HPV 1620 µg HPV 16 20 µg HPV 1820 µg HPV 18 0, 1, 6 months0, 1, 6 months 20 µg HPV 620 µg HPV 6 40 µg HPV 1140 µg HPV 11 40 µg HPV 1640 µg HPV 16 20 µg HPV 1820 µg HPV 18 0, 2, 6 months0, 2, 6 months AdjuvantAdjuvant 500 µg Aluminum Hydroxide w/500 µg Aluminum Hydroxide w/ 50 µg 3-deacylated50 µg 3-deacylated monophosphoryl lipid A (AS04)monophosphoryl lipid A (AS04) 225 µg Aluminum225 µg Aluminum Hydroxyphosphate SulfateHydroxyphosphate Sulfate
    • 25. Quadrivalent HPV vaccine
    • 26. Quadrivalent HPV vaccine
    • 27. Quadrivalent HPV vaccine
    • 28. J Cohen, Science 2005:308; 618-621
    • 29. Quadrivalent HPV vaccine
    • 30. Prophylactic HPV vaccination of HIV-seropositive men and women  Does the vaccine prevent anal HPV infectionDoes the vaccine prevent anal HPV infection and AIN?and AIN?  Should all men be vaccinated so that MSMShould all men be vaccinated so that MSM are protected before onset of sexual activity?are protected before onset of sexual activity?
    • 31. Prophylactic HPV vaccination of HIV-seropositive men and women  Is vaccination safe?Is vaccination safe?  Can HIV-seropositive individuals mount andCan HIV-seropositive individuals mount and maintain protective titers against HPV?maintain protective titers against HPV?  Is there sufficient HPV DNA- and sero-Is there sufficient HPV DNA- and sero- negativity to provide for vaccine efficacy?negativity to provide for vaccine efficacy?
    • 32. Slide 35
    • 33. Slide 36